The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis

Studies have shown that immune responses are depressed in male mice, but no t in proestrus females after trauma-hemorrhage (TH), resulting in increased mortality from subsequent sepsis in male mice compared with female mice. T hese gender-specific alterations in immune function are believed to be due to differences in sex steroid levels. Aromatase is a key enzyme in the sex steroid biosynthesis. Although earlier studies have shown that aromatase in hibitors prevent thymic atrophy in aged male rats, it remains unknown wheth er the use of 4-hydroxy-androstenedione (4-OHA) after TH in male mice has a ny salutary effects on the depressed immune responses. Male C3H/HeN mice we re sham operated or subjected to trauma (i.e., midline laparotomy) and hemo rrhagic shock (30 +/- 5 mmHg for 90 min) followed by adequate fluid resusci tation, 4-OHA (5 mg/kg) or vehicle was administrated s.c. just before resus citation. At 2 h after resuscitation, the mice were killed, and spleens wer e harvested. Splenocyte proliferation, interleukin (IL-2), interferon (IFN- gamma), and IL-10 release and expression of androgen (AR) and estrogen rece ptors (ER)-alpha and -beta by immunoblot and reverse transcription-polymera se chain reaction (RT-PCR) were assessed. In another group, sepsis was indu ced by cecal ligation and puncture (CLP) 3 days after resuscitation, and su rvival was measured over a period of 10 days. A significant decrease in spl enocyte proliferation, IL-2, and IFN-gamma release and increased release of IL-10 were observed in vehicle-treated mice. Animals treated with 4-OHA sh owed increased splenocyte proliferation. IL-2, and IFN-gamma release, and d ecreased IL-10 release. Immunoblot analysis showed decreased expression of the cytosolic AR, but no significant difference in the cytosolic and nuclea r ER-alpha and -beta expression was observed in the vehicle-treated group a fter TH. In addition, AR and ER-beta mRNA expression was increased, whereas ER-alpha expression decreased in the vehicle-treated group after TH, ER-al pha expression decreased and ER-beta expression increased in the nucleus of 4-OHA treated mice as determined by immunoblot. There was no difference in the cytosolic AR expression in the 4-OHA-treated group after TH. AR and ER -beta mRNA expression was unaffected, whereas ER-alpha expression increased under such conditions. In additional groups, the increased mortality rate after TH and subsequent sepsis was significantly reduced by 4-OHA treatment . Thus, 4-OHA seems to be a novel and useful adjunct for restoring the depr essed immune functions in males after TH and for decreasing mortality rates from subsequent sepsis.